Safety of β2-Agonists in Asthma: Linking Mechanisms, Meta-Analyses and Regulatory Practice
Journal Title: The AAPS Journal - Year 2015, Vol 17, Issue 3
Abstract
An epidemic of asthma fatalities in the 1970s prompted a series of case-control studies which indicated that short acting β-agonists increased the risk of death. Subsequent mechanistic and pharmacodynamic studies have suggested that β-agonist monotherapy facilitates airway inflammation, although when co-administered with inhaled corticosteroids (ICSs), similar evidence is lacking. The Salmeterol Multicenter Asthma Research Trial, which revealed a fourfold increase in asthma-related deaths in salmeterol-treated patients, prompted a paradigm shift in the evidential assessment of β-agonist safety. The FDA’s meta-analysis of over 60,000 patients ultimately concluded that long-acting β-agonist (LABA) therapy increased the risk of serious asthma-related events. However, this meta-analysis itself raised questions given a large body of omitted data and a limited emphasis on the risk of ICS-LABA co-administration. Subsequently, the FDA mandated the conduct of five large studies to definitively ascertain whether ICS-LABAs increase asthma-related risk. Whether this ambitious programme will provide certainty remains to be seen given issues of multiplicity, the very low frequency of fatal and near-fatal asthma, and the administration of a free combination of ICS and LABA in one trial. The FDA’s de facto use of FEV1 as a safety parameter, based on findings from the Foradil NDA, is a further topical issue: subsequent clinical study data, considerations relating to regional pulmonary drug deposition and pharmacological differences between different β-agonists suggest that FEV1 may be a suboptimal safety metric. Models evaluating airway inflammation and bronchial reactivity may be more appropriate to assess the relative risk of asthma-related events.
Authors and Affiliations
Sanjeeva. B. Dissanayake
Keywords
Related Articles
- EP ID EP680960
- DOI 10.1208/s12248-015-9734-8
- Views 74
- Downloads 0
Early Drug Discovery Prediction of Proarrhythmia Potential and Its Covariates
Region-Dependent Role of Cell-Penetrating Peptides in Insulin Absorption Across the Rat Small Intestinal Membrane
We have reported that the cell-penetrating peptide (CPP) penetratin acts as a potential absorption enhancer in oral insulin delivery systems and that this action occurs through noncovalent intermolecular interactions. Ho...
A Sensitivity Analysis of the Modified Chi-square Ratio Statistic for Equivalence Testing of Aerodynamic Particle Size Distribution
The online version of this article (doi:10.1208/s12248-013-9453-y) contains supplementary material, which is available to authorized users.
Is any measurement method optimal for all aggregate sizes and types?
Protein-based pharmaceuticals exhibit a wide range of aggregation phenomena, making it virtually impossible to find any one analytical method that works well in all cases. Aggregate sizes cover a range from small oligome...
Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics
Opioids are widely used in the treatment of severe pain. The clinical use of the opioids is limited by serious side effects such as respiratory depression, constipation, development of tolerance, and physical dependence...